Much progress has been made toward the understanding of human acquired immune deficiency syndrome (AIDS). The causitive agent, a retrovirus, has been isolated, the nucleotide sequence of several isolates has been determined, and novel genes have been identified. In spite of these advances, much still needs to be learned regarding the genetic determinants of pathogenicity and mechanisms of pathogenesis. Progress in these areas can best be achieved through the use of suitable animal models. Simian immunodeficiency virus (SIV) isolated from macaques is very similar to HIV in its biological properties and the two viruses are related antigenically. SIV also causes AIDS in common rhesus monkeys. It thus appears that SIV of macaques is very useful for human AIDS research. In this proposal, infectious clones of different SIV isolates will be obtained through the molecular cloning of the integrated provirus. Their nucleotide sequences will be determined. The in vitro biological properties and in vivo pathogenic potential of viruses derived form these molecular clones will be compared. Hybrid SIVs will be constructed between viruses with different biological properties and pathogenic potential, so that the nucleotide sequence responsible for the pathogenicity and other biological properties can be identified. To further study the molecular genetics of the viral genes and to confirm nucleotide sequences important for pathogenicity, deletion and insertion mutants will be constructed and site-specific in vitro mutagenesis will be performed so that important nucleotide sequences can be recognized. This research has important long term consequences for development of antiviral drugs to treat the infected, and safe and effective vaccines to protect virus and its pathogenicity will greatly facilitate the development of therapeutic drugs and effective vaccines.